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Biomedicine & Pharmacotherapy 67 (2013) 179–182
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Review
The urokinase plasminogen activator system in breast cancer invasion and
metastasis
Linlin Tang a, Xiuzhen Han a,*,b
a
b
Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44, West Wenhua Road, Jinan, Shandong Province 250012, China
Key Laboratory of Chemical Biology of Natural Products, Ministry of Education, Shandong University, 44, West Wenhua Road, Jinan 250012, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 1 September 2012
Accepted 22 October 2012
The urokinase plasminogen activator system, which is a serine protease family include urokinase-type
plasminogen activator (uPA), the uPA receptor and plasminogen activator inhibitors (PAIs). uPA
catalyzes the transformation of plasminogen to its active form plasmin, which is able to degrade the
extracellular matrix (ECM) and basement membranes, directly or indirectly through activating promatrix metalloproteinases (pro-MMPs), promoting cancer cell metastasis and invasion. Both uPA and
PAI-1 are poor prognosis markers in primary breast cancer. Evidence has been presented that the uPA
system facilitates breast cancer metastasis by several different mechanisms, such as the Ras-ERK
pathway and p38 MAPK pathway. This review focuses on uPA system, summarizes their biological
effects, highlights the molecular mechanism and pathway, and discusses the role of uPA system in the
prevention and treatment of human breast cancers.
ß 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
uPA system
Breast cancer
Metastasis
Invasion
Ras-ERK pathway
1. Introduction
2. The urokinase plasminogen activator system
Breast cancer is one of the major malignant tumors to threaten
women well being. About 25 to 40% of breast cancer patients
develop distant metastases [1]. Various proteolytic enzymes play
an important action in tumor invasion and metastasis process.
These proteases involve collagenases, cathepsins, plasmin, or
plasminogen activators [2]. The urokinase plasminogen activator
(uPA) system, which is a serine protease family, plays a crucial role
in tumor invasion and metastasis. The system includes urokinasetype plasminogen activator (uPA), the glycolipid-anchored cell
membrane receptor for the uPA (uPAR), plasminogen activator
inhibitors (PAIs). The biological system is implicated in multiple
physiological and pathologic processes including cell migration,
angiogenesis, inflammation, embryogenesis, tumor growth, and
metastasis [3]. uPA and uPAR were over-expressed in diverse
human malignant tumors in contrast to the corresponding normal
tissue. The uPA system catalyzes the inactive plasminogen to the
active plasmin, which lead to the degradation and regeneration of
the basement membrane and extracellular matrix (ECM) that
result in metastasis. It is beyond reasonable doubt that this enzyme
system plays a central role in tumor biology and represents a high
potential target for therapeutic intervention of tumor growth and
metastasis.
2.1. uPA
uPA protein is 411 amino acid residues long, consists of two a
helices and two anti-parallel b strands, and is secreted as a 53 KD
zymogen (pro-urokinase) [4]. The pro-uPA is an one-chain zymogen,
with an activity that is at least several hundred-fold lower than that
of two-chain uPA. The former consists of two disulfide bridge–linked
polypeptide chains; a carboxyl terminal serine proteinase domain
and an amino terminal contained a kringle and a growth factor
domain (GFD). The GFD contains all the determinants required for
binding to uPAR. Conversion of pro-uPA to uPA occurs by cleavage of
the peptide bond Lys158–Ile159. This conversion can be catalyzed
by plasmin. In turn, uPA can catalyze the inactive plasminogen to the
active plasmin though splitting the single peptide bond Arg561Val562. Thus, uPA and plasmin generate a positive feedback loop to
active each other [5]. The serine proteinase plasmin consists of two
disulfide bridge–linked polypeptide chains. The C-terminal contains
a typical serine proteinase domain which is responsible for catalytic
activity and binding to inhibitors. The N-terminal contains five socalled kringle domains. Plasmin is able to be inhibited by a2-antiplasmin (a2AP) [6].
2.2. uPAR
* Corresponding author. Tel.: +86 531 88382490; fax: +86 531 88382490.
E-mail addresses: [email protected], [email protected] (X. Han).
0753-3322/$ – see front matter ß 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.biopha.2012.10.003
uPAR is over-expressed in various tumour cells, including colon,
liver, breast, lung, stomach, ovary cancer et al.; additionally in
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L. Tang, X. Han / Biomedicine & Pharmacotherapy 67 (2013) 179–182
several tumour assisting cells, such as endothelial cells, macrophages and fibroblasts [7]. uPAR is a 50–60 kDa extracellular
glycoprotein with riched cysteine and congregated in lipid rafts [8].
uPAR is composed of three homologous domains (D1, D2 and D3)
belonging to the Ly-6/uPAR/alpha-neurotoxin protein domain
family [9], the last of which attached to the cell membrane by a
glycosyl phosphatidyl inositol (GPI) anchor. This GPI-anchor is
hypothesized to have high intramembrane mobility. Furthermore,
the uPAR is glycosylated at N-residues of glucosamine and sialic
acid within the binding site, thereby regulating its affinity (KD of
0.1–1.0 nM) for uPA [10]. uPAR binds with high affinity to uPA, prouPA and the ECM protein vitronectin. The interaction between uPA
and uPAR require the intact three-domain (D1, D2 and D3)
structure of uPAR, among which D1 is most important during the
interaction. The crystal structure of a soluble form of human uPAR
reveals that the receptor-binding module of uPA engages the uPAR
central cavity, thus leaving the external receptor surface accessible
for vitronectin (VN) and integrins [11]. uPAR shed from the
membrane by phospholipase or proteolytic cleavage the GPIanchor. The soluble uPAR can scavenge the uPA and interfere in the
functions of uPAR [12]. The release of DI fragment from the rest
receptor (DIIDIII) induces uPAR cleavage, which inactivate the
binding to most ligands [13].
2.3. Serine proteinase inhibitor
The activation of uPA and tissue plasminogen activator (tPA) can
be inhibited by the endogenous serine proteinase inhibitor PAI-1
and PAI-2 among which the fast acting PAI-1plays the predominant
role [10]. PAI-1 reacts quickly with both uPA and tPA [6], modulating
the fibrinolytic activity in the vasculature. PAI-1 is mainly produced
by endothelial cells, megakaryocytes as well as smooth muscle cells
and stored in platelets [14]. After release into the bloodstream, the
majority of PAI-1 is active and circulates in complex with VN [15].
PAI-1 binds active uPA forming an uPAR-uPA-PAI-1 covalent
complex and brings about the internalization of the whole complex.
This internalization is mediated by a member of the low density
lipoprotein receptor-related protein (LRP) family. This process
involves the formation of clathrin-coated vesicles; uPA-PAI-1
complex is degraded in lysosomes and uPAR is recycled back to
the cell surface, which is necessary to sustain plasminogen
activation on the cell surface [4,16,17]. PAIs react with active uPA,
but not with pro-uPA [18]. PAI-1 and u-PAR can interact with the
ECM protein VN and its integrin [6]. VN contains one somatomedin B
(SMB) domain, one Arg-Gly-Asp (RGD) sequence, one collagenbinding region and two hemopexin-like domains [19]. The SMB
domain binds PAI-1 and u-PAR and the RGD sequence binds the
integrins. PAI-1 and u-PAR can compete for binding to VN. And PAI-1
may impair the binding of integrins to VN.
3. Biological functions
uPA catalyzes the transformation of plasminogen to its active
form plasmin, which is able to degrade many ECM proteins, such as
fibronectin (FN), VN and fibrin. It can also catalyze activation of the
zymogen forms of several metalloproteinases [6]. In this regard,
uPA may have a central role in initiating the proteolytic cascade
that facilitates the invasion of blood vessels by tumor cells, their
dissemination through the circulation, and their final deposition
and growth at distant sites [20]. uPA triggers the series cascade
reactions relying on combination with uPAR. The effect of uPAR on
cancer cell migration may be divided into proteolytic as well as
non-proteolytic functions. The proteolytic function catalyze by
uPAR-bound uPA. The non-proteolytic function will rely on the
interaction with VN, integrin family and G protein-coupled
receptors [21]. The total functions of uPAR contain cellular
movement by proteolytic extracellular matrix degradation for
tumor cell invasion, chemotaxis, and cellular adhesion; activation
diacylglycerol accumulation, modulation of cAMP levels, angiogenesis, and alterations in inositol phosphate, interactions with
integrins, tyrosine kinases and serine/threonine kinases [8,22]. The
uPAR also have influence the development of inflammatory and
immune responses [17]. Cells are resistant to traditional chemotherapies, and could serve as critical targets for more effective
therapeutic interventions [23]. The data of Hollas et al. suggest that
invasion is a function of the amount of cell surface receptor bound
urokinase for cultured colon cancer [24]. uPAR activates various
intracellular signaling molecules such as the tyrosine kinase Src,
the serine kinase Raf, focal adhesion kinase (FAK), p130Cas and
extracellular-signal-regulated kinase (ERK)/mitogen-activated
protein kinase (MAPK). Activation of these proteins leads to deep
changes in cell proliferation, adhesion and metastasis [12]. PAI-1’s
role in cancers is dual character that it can affect cell surface
expression and internalization of uPA-uPAR leading to inhibition of
invasion and metastasis and also it has been reported to facilitate
tumor growth and dissemination [4]. PAI-1 is a poor prognostic
marker in various tumors. PAI-1 promotes cancer invasion and
metastasis through preventing excess degradation of the ECM,
modulating cell adhesion, playing a role in angiogenesis, and
stimulating cell proliferation [25].
4. uPA system and breast cancer
uPA is involved in regulating breast cancer invasion and
metastasis, explained by its ability to facilitate ECM degradation,
cell proliferation, angiogenesis, migration and adhesion[26,27].
The traditional prognostic factors for breast cancer focus on age,
tumor size, tumor grade, lymph node status, steroid receptor
status, menopausal status and histologic type [25,28]. uPA and
PAI-1 are the first novel tumor biological prognostic factors
confirmed in the highest level of evidence regarding their clinical
utility in breast cancer[29]. As a marker for breast cancer, uPA may
be an important independent variable to identify the recurrence
rate [2] and is stronger than most of the traditional prognostic
factors [25], especially in the node-negative subtype. uPA and PAI1 can classify about half of node-negative breast cancer patients as
low risk, of which low levels have a very good prognosis, and half
as high risk, because of high levels of them are correlated with
shortened disease-free interval and poor overall survival [30,31].
uPA and PAI-1 play a key role in selecting appropriate therapies for
patients with breast cancer[25]. High concentrations of uPA and
PAI-1 in node-negative breast cancer women could benefit from
adjuvant chemotherapy, whereas those with low concentrations
of both proteins could be spared the side effects and costs of this
treatment [25]. Node-negative patients with high uPA/PAI-1 are
more than double risk of disease recurrence compared to that of
patients with three or more tumor cell positive axillary lymph
nodes [31]. Some study showed the bad prognostic impact of high
uPA and PAI-1 levels was higher in patients treated with adjuvant
chemotherapy than patients treated with adjuvant hormone
therapy [32], while other results suggested that patients with
increased concentrations of either uPA or PAI-1 fail to respond to
hormone therapy in advanced disease [25]. In lymph nodepositive patients, PAI-1 protein displayed stronger prognostic
impact than uPA [33]. uPA and PAI-1 median levels are higher in
ductal than in lobular tumors[28]. In conclusion, uPA and PAI-1
levels in primary tumor tissue provide clinically relevant
information on relapse risk and treatment response that will
help to tailor adjuvant therapy concepts in breast cancer,
accounting for individual biological tumor characteristics [34].
L. Tang, X. Han / Biomedicine & Pharmacotherapy 67 (2013) 179–182
181
Fig. 1. Schematic representation of components and biological functions about uPA system.
5. Mechanisms of uPA system in cancer invasion and
metastasis
The uPA system promotes tumor metastasis by several different
mechanisms (Fig. 1), and not just only by breaking down the ECM
[35]. uPA and uPAR initiate the activation of MMPs as well as the
conversion of plasminogen to plasmin [36], then degradate the ECM
and reduce the interaction between cell and cell, cell and ECM.
Expression of uPA and uPAR can be up-regulated by mitogen, growth
factors, the oncogenes v-Src and v-Ras, cytokines, protein kinase C
and ligation of integrin with extracellular matrix protein [37,38].
Binding of uPA to uPAR can activate Ras-Raf-MEK-ERK pathway
[39]. Because uPAR has no transmembrane structure, many studies
propose integrins act as an associated protein to transduce
proliferative or migratory signals [40,41]. In the transduction
events, some intracelluar enzymes and adaptor proteins should
play key roles in the signal transduction processes. The FAK has
been implicated to mediate signal transduction events initiated by
integrins through recruitment c-Src or other Src family tyrosine
kinases [42]. Src phosphorylates Tyr-925 in FAK and creates a
binding site for Grb2/Sos complex to activate Ras. c-Src and FAK
may also phosphorylate Shc serving as an adaptor protein to
recruit Grb2. FAK, c-Src, and Shc affiliates the uPAR-initiated
pathway and integrin-mediated ERK activation [43]. uPA-induced
Ras-ERK signaling pathway is dependent on the downstream
effectors Raf and MEK [44]. uPA-initiated cell migration requires
the integration of diverse cell signaling pathways. Jo et al. support
Rho-Rho kinase pathway cooperates to promote Ras-ERK-stimulated cell migration [44]. The p38 MAPK pathway also participates
in uPA secretion and inhibits the MEK/ERK signaling pathway [45].
Myosin light chain kinase (MLCK) acts as downstream of Ras/ERK
and involves in uPA-promoted cell migration. Activated MLCK can
induce serine phosphorylation of the myosin II regulatory light
chain and thereby promotes contraction of the actomyosin
cytoskeleton [44].
There are other signal pathways involved in uPA-initiated cell
migration to be reported. Present studies suggest that the p38
MAPK pathway participates in invasive breast cell migration by
regulating uPA expression. p38a, rather than p38b, MAPK activity
is essential for uPA expression [36]. The Rac1-MKK3-p38MAPKAPK2 pathway was found to mediate Vn/av integrinmediated uPA up-regulation [46]. Bagheri-Yarmand et al. showed
that upregulation of the uPA system contributed to the invasive
function of LIMK1 in MDA-MB-435 breast cancer cells and
suggested a signaling pathway connecting LIMK1 and the uPA
system to actin reorganization and increased cell invasiveness
[47]. Another reporter showed that uPA transcription was
regulated through canonical JAG- Notch signaling, facilitating
the invasion and metastasis in breast cancer [3]. In MDA-MB-231
cells, active PI3K, via transactivation of NF-kB, induces expression
and secretion of uPA. PI3K is constitutively active in highly invasive
breast cancer cell, MDA-MB-231[48]. And PKC through the active
transcription factors AP-1 and NF-kB regulates secretion of uPA in
breast cancer cells [38]. The correlation between PAI-1 and integrin
aV and HER3 also were found [49,50].
6. Conclusion
uPA system plays an important role in breast cancer growth,
invasion, and metastasis. As a candidate target, uPA is crucial in the
choice of adjuvant therapy scheme in node-negative breast cancer
because it provides relevant information on relapse risk and
treatment response. uPA system may be worked through Ras-ERK
or p38-MAPK pathway to facilitate tumor cell metastasis and
invasion, but it need to be further investigated.
Disclosure of interest
The authors declare that they have no conflicts of interest
concerning this article.
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L. Tang, X. Han / Biomedicine & Pharmacotherapy 67 (2013) 179–182
Acknowledgements
[28]
This work was supported by Independent Innovation Foundation of Shandong University (No. 2012ZD043), the Natural Science
Foundation of Shandong Province (No.Y2007C098) and the
Technology Development Planning of Shandong Province (No.
2009GG10002083) of P.R.China.
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